p-Xylylenedicyanide and related compounds,weakly cytotoxic nitriles

Zusammenfassung Extrakte vonV. opulus von schwacher Zelltoxizität enthaltenp-Xylylendinitril. Die Isomeren,m- undp-Cyanohydrozimtsäurenitrile, wurden synthetisiert und auf ihre zelltoxischen Eigenschaften hin untersucht:p-Xylylendinitril erweist sich als am stärksten wirksam.

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The reported work was supported in part by grants Nos. AM 07147, FR 00354, GM 12755 and GM 33888 from the United States Public Health Service, National Institutes of Health. We are grateful to the management and staff of the Isaac Bernheim Foundation for their helpful assistance with plants.

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Inquiries on mass spectra should be directed to F.W.M.; all other inquiries should be directed to C.H.J.     

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.     

Dispersal and extraterritorial movements of swift foxes ( Vulpes velox ) in northwestern Texas

Dispersal plays an important role in the population dynamics of many carnivores, yet little information exists about the dispersal and movement patterns of swift foxes ( Vulpes velox ). We radio-collared and monitored 68 swift foxes for dispersal at 2 study sites in northwestern Texas from January 2002 to April 2004. Dispersal distance for juveniles (13.1 ± 0.3 km, s ), adults (10 ± 4.7 km) and transients (25.4 ± 9.1 km) did not differ by age class ( F = 1.49, df = 2, P = 0.24) or sex ( F = 0.23, df = 1, P = 0.63) but differed by study site ( F = 4.72, df = 1, P = 0.04). Mean dispersal distance from private ranches (PR) was greater than from National Grasslands (NG). Peak dispersal occurred during October– November (13 individuals) and January–February (7 individuals). Dispersal direction was influenced by land-use practices (i.e., toward rangelands and away from anthropogenic features). Direction of dispersal among foxes that occupied the NG was uniform ( n = 16, P = 0.08), whereas foxes from PR dispersed in a northwesterly direction ( n = 18, P ≤ 0.001) away from a town and croplands. Three resident adult foxes made extraterritorial movements. Distances of these movements ranged from 0.2 km to 11.4 km. Distance of extraterritorial movements did not differ by sex ( F = 0.05, P = 0.83), nor by duration of movement ( F = 1.11, P = 0.32). Knowledge of movement distances and patterns is important for conservation and protection of swift foxes and their habitats.     

Two homologous protein components of hepatic gap junctions

Gap junctions consist of closely packed pairs of transmembrane channels, the connexons, through which materials of low relative molecular mass diffuse from the cell to neighbouring cells. In liver, connexons consist of six protein subunits which, until now, were believed to be identical. However, besides the major polypeptide of relative molecular mass (Mr) 28,000 (and see refs 4 and 6), a component of Mr 21,000 (21K) has been repeatedly observed in liver. The amino-terminal sequence (18 residues) of this less abundant protein shows that it is related to, but distinct from, the Mr 28K protein. Immuno-staining and immuno-precipitation show both proteins to be in the same gap junctional plaques. Thus, it seems that hepatic gap junction channels (and by extension possibly others) are composed of two (or more) homologous proteins.     

Pharmaco-metabonomic phenotyping and personalized drug treatment

There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.